Methods of treating term and near-term neonates having hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension

ABSTRACT

The invention relates methods of reducing the risk or preventing the occurrence of an adverse event (AE) or a serious adverse event (SAE) associated with a medical treatment comprising inhalation of nitric oxide.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. patent application Ser. No.12/494,598, entitled “Methods of Treating Term and Near-Term NeonatesHaving Hypoxic Respiratory Failure Associated with Clinical orEchocardiographic Evidence of Pulmonary Hypertension”, filed on Jun. 30,2009, incorporated herein by reference.

BACKGROUND OF THE INVENTION

INOmax®, (nitric oxide) for inhalation is an approved drug product forthe treatment of term and near-term (>34 weeks gestation) neonateshaving hypoxic respiratory failure associated with clinical orechocardiographic evidence of pulmonary hypertension.

The use of inhaled NO (iNO) has been studied and reported in theliterature. (Kieler-Jensen M et al., 1994, Inhaled Nitric Oxide in theEvaluation of Heart Transplant Candidates with Elevated PulmonaryVascular Resistance, J Heart Lung Transplantation 13:366-375; Pearl R Get al., 1983, Acute Hemodynamic Effects of Nitroglycerin in PulmonaryHypertension, American College of Physicians 99:9-13; Ajami G H et al.,2007, Comparison of the Effectiveness of Oral Sildenafil Versus OxygenAdministration as a Test for Feasibility of Operation for Patients withSecondary Pulmonary Arterial Hypertension, Pediatr Cardiol;Schulze-Neick I et al., 2003, Intravenous Sildenafil Is a PotentPulmonary Vasodilator in Children With Congenital Heart Disease,Circulation 108 (Suppl II):II-167-II-173; Lepore J J et al., 2002,Effect of Sildenafil on the Acute Pulmonary Vasodilator Response toInhaled Nitric Oxide in Adults with Primary Pulmonary Hypertension, TheAmerican Journal of Cardiology 90:677-680; and Ziegler J W et al., 1998,Effects of Dipyridamole and Inhaled Nitric Oxide in Pediatric Patientswith Pulmonary Hypertension, American Journal of Respiratory andCritical Care Medicine 158:1388-95).

SUMMARY OF THE INVENTION

One aspect of the invention relates to a pre-screening methodology orprotocol having exclusionary criteria to be evaluated by a medicalprovider prior to treatment of a patient with iNO. One objective of theinvention is to evaluate and possibly exclude from treatment patientseligible for treatment with iNO, who have pre-existing left ventriculardysfunction (LVD). Patients who have pre-existing LVD may experience,and are at risk of, an increased rate of adverse events or seriousadverse events (e.g., pulmonary edema) when treated with iNO. Suchpatients may be characterized as having a pulmonary capillary wedgepressure (PCWP) greater than 20 mm Hg, and should be evaluated on acase-by-case basis with respect to the benefit versus risk of using iNOas a treatment option.

Accordingly, one aspect of the invention includes a method of reducingthe risk or preventing the occurrence, in a human patient, of an adverseevent (AE) or a serious adverse event (SAE) associated with a medicaltreatment comprising inhalation of nitric oxide, said method comprisingthe steps or acts of (a) providing pharmaceutically acceptable nitricoxide gas to a medical provider; and, (b) informing the medical providerthat excluding human patients who have pre-existing left ventriculardysfunction from said treatment reduces the risk or prevents theoccurrence of the adverse event or the serious adverse event associatedwith said medical treatment.

Further provided herein is a method of reducing the risk or preventingthe occurrence, in a human patient, of an adverse event or a seriousadverse event associated with a medical treatment comprising inhalationof nitric oxide, said method comprising the steps or acts of (a.)providing pharmaceutically acceptable nitric oxide gas to a medicalprovider; and, (b.) informing the medical provider that human patientshaving pre-existing left ventricular dysfunction experience an increasedrisk of serious adverse events associated with said medical treatment.

Another aspect of the invention is a method of reducing one or more ofan AE or a SAE in an intended patient population in need of beingtreated with iNO comprising the steps or acts of (a.) identifying apatient eligible for iNO treatment; (b) evaluating and screening thepatient to identify if the patient has pre-existing LVD, and (c)excluding from iNO treatment a patient identified as having pre-existingLVD.

Another aspect of the invention is a method of reducing the risk orpreventing the occurrence, in a patient, of one or more of an AE or aSAE associated with a medical treatment comprising iNO, the methodcomprising the steps or acts of (a.) identifying a patient in need ofreceiving iNO treatment; (b.) evaluating and screening the patient toidentify if the patient has pre-existing LVD; and (c.) administering iNOif the patient does not have pre-existing LVD, thereby reducing the riskor preventing the occurrence of the AE or the SAE associated with theiNO treatment. Alternatively, step (c) may comprise further evaluatingthe risk versus benefit of utilizing iNO in a patient where the patientshas clinically significant LVD before administering iNO to the patient.

In an exemplary embodiment of the method, the method further comprisesinforming the medical provider that there is a risk associated withusing inhaled nitric oxides in human patients who have preexisting orclinically significant left ventricular dysfunction and that such riskshould be evaluated on a case by case basis.

In another exemplary embodiment of the method, the method furthercomprises informing the medical provider that there is a risk associatedwith using inhaled nitric oxide in human patients who have leftventricular dysfunction.

In an exemplary embodiment of the methods described herein, a patienthaving pre-existing LVD is characterized as having PCWP greater than 20mm Hg.

In an exemplary embodiment of the method, the patients havingpre-existing LVD demonstrate a PCWP≧20 mm Hg.

In another exemplary embodiment of the method, the iNO treatment furthercomprises inhalation of oxygen (O₂) or concurrent ventilation.

In another exemplary embodiment of the method, the patients havingpre-existing LVD have one or more of diastolic dysfunction, hypertensivecardiomyopathy, systolic dysfunction, ischemic cardiomyopathy, viralcardiomyopathy, idiopathic cardiomyopathy, autoimmune disease relatedcardiomyopathy, drug-related cardiomyopathy, toxin-relatedcardiomyopathy, structural heart disease, valvular heart disease,congenital heart disease, or, associations thereof.

In another exemplary embodiment of the method, the patient populationcomprises children.

In another exemplary embodiment of the method, the patient populationcomprises adults.

In another exemplary embodiment of the method, the patients who havepre-existing LVD are at risk of experiencing and increased rate of oneor more AEs or SAEs selected from pulmonary edema, hypotension, cardiacarrest, electrocardiogram changes, hypoxemia, hypoxia, bradycardia orassociations thereof.

In another exemplary embodiment of the method, the intended patientpopulation in need of being treated with inhalation of nitric oxide hasone or more of idiopathic pulmonary arterial hypertension characterizedby a mean pulmonary artery pressure (PAPm)>25 mm Hg at rest, PCWP≦15 mmHg, and, a pulmonary vascular resistance index (PVRI)>3 u·m²; congenitalheart disease with pulmonary hypertension repaired and unrepairedcharacterized by PAPm>25 mm Hg at rest and PVRI>3 u·m²; cardiomyopathycharacterized by PAPm>25 mm Hg at rest and PVRI>3 u·m²; or, the patientis scheduled to undergo right heart catheterization to assess pulmonaryvasoreactivity by acute pulmonary vasodilatation testing.

In another exemplary embodiment of any of the above methods, the methodfurther comprises reducing left ventricular afterload to minimize orreduce the risk of the occurrence of an adverse event or serious adverseevent being pulmonary edema in the patient. The left ventricularafterload may be minimized or reduced by administering a pharmaceuticaldosage form comprising nitroglycerin or calcium channel blocker to thepatient. The left ventricular afterload may also be minimized or reducedusing an intra-aortic balloon pump.

DETAILED DESCRIPTION OF THE EXEMPLARY EMBODIMENTS

INOmax® (nitric oxide) for inhalation was approved for sale in theUnited States by the U.S. Food and Drug Administration (“FDA”) in 1999.Nitric oxide, the active substance in INOmax®, is a selective pulmonaryvasodilator that increases the partial pressure of arterial oxygen(PaO₂) by dilating pulmonary vessels in better ventilated areas of thelung, redistributing pulmonary blood flow away from the lung regionswith low ventilation/perfusion (V/Q) ratios toward regions with normalratios. INOmax® significantly improves oxygenation, reduces the need forextracorporeal oxygenation and is indicated to be used in conjunctionwith ventilatory support and other appropriate agents. The currentFDA-approved prescribing information for INOmax® is incorporated hereinby reference in its entirety.

INOmax® is a gaseous blend of NO and nitrogen (0.08% and 99.92%respectively for 800 ppm; and 0.01% and 99.99% respectively for 100 ppm)and is supplied in aluminium cylinders as a compressed gas under highpressure. In general, INOmax® is administered to a patient inconjunction with ventilatory support and O₂. Delivery devices suitablefor the safe and effective delivery of gaseous NO for inhalation includethe INOvent®, INOmax DS®, INOpulse®, INOblender®, or other suitable drugdelivery and regulation devices or components incorporated therein, orother related processes, which are described in various patent documentsincluding U.S. Pat Nos. 5,558,083; 5,732,693; 5,752,504; 5,732,694;6,089,229; 6,109,260; 6,125,846; 6,164,276; 6,581,592; 5,918,596;5,839,433; 7,114,510; 5,417,950; 5,670,125; 5,670,127; 5,692,495;5,514,204; 7,523,752; 5,699,790; 5,885,621; U.S. patent application Ser.Nos. 11/355,670 (US 2007/0190184); 10/520,270 (US 2006/0093681);11/401,722 (US 2007/0202083); 10/053,535 (US 2002/0155166); 10/367,277(US 2003/0219496); 10/439,632 (US 2004/0052866); 10/371,666 (US2003/0219497); 10/413,817 (US 2004/0005367); 12/050,826 (US2008/0167609); and PCT/US2009/045266, all of which are incorporatedherein by reference in their entirety.

Such devices deliver INOmax® into the inspiratory limb of the patientbreathing circuit in a way that provides a constant concentration of NOto the patient throughout the inspired breath. Importantly, suitabledelivery devices provide continuous integrated monitoring of inspiredO₂, NO₂ and NO, a comprehensive alarm system, a suitable power sourcefor uninterrupted NO delivery and a backup NO delivery capability.

As used herein, the term “children” (and variations thereof) includesthose being around 4 weeks to 18 years of age.

As used herein, the term “adult” (and variations thereof) includes thosebeing over 18 years of age.

As used herein, the terms “adverse event” or “AE” (and variationsthereof) mean any untoward occurrence in a subject, or clinicalinvestigation subject administered a pharmaceutical product (such asnitric oxide) and which does not necessarily have a causal relationshipwith such treatment. An adverse event can therefore be any unfavorableand unintended sign (including an abnormal laboratory finding), symptom,or disease temporarily associated with the use of amedicinal/investigational product, whether or not related to theinvestigational product. A relationship to the investigational productis not necessarily proven or implied. However, abnormal values are notreported as adverse events unless considered clinically significant bythe investigator.

As used herein, the terms “adverse drug reaction” or “ADR” (andvariations thereof) mean any noxious and unintended response to amedicinal product related to any dose.

As used herein, the terms “serious adverse event” or “SAE” (or “seriousadverse drug reaction” or “serious ADR”) (and variations thereof) mean asignificant hazard or side effect, regardless of the investigator'sopinion on the relationship to the investigational product. A seriousadverse event or reaction is any untoward medical occurrence that at anydose: results in death; is life-threatening (which refers to anevent/reaction where the patient was at risk of death at the time of theevent/reaction, however this does not refer to an event/reaction thathypothetically may have caused death if it were more severe); requiresinpatient hospitalization or results in prolongation of existinghospitalization; results in persistent or significantdisability/incapacity; is a congenital anomaly/birth defect; or, is amedically important event or reaction. Medical and scientific judgmentis exercised in deciding whether reporting is appropriate in othersituations, such as important medical events that may not be immediatelylife threatening or result in death or hospitalization but mayjeopardize the subject or may require medical or surgical interventionto prevent one of the other outcomes listed above—these are alsoconsidered serious. Examples of such medical events include cancer,allergic bronchospasm requiring intensive treatment in an emergency roomor at home, blood dyscrasias or convulsions that do not result inhospitalizations, or the development of drug dependency or drug abuse.Serious clinical laboratory abnormalities directly associated withrelevant clinical signs or symptoms are also reported.

Left Ventricular Dysfunction. Patients having pre-existing LVD may bedescribed in general as those with elevated pulmonary capillary wedgepressure, including those with diastolic dysfunction (includinghypertensive cardiomyopathy), those with systolic dysfunction, includingthose with cardiomyopathies (including ischemic or viral cardiomyopathy,or idiopathic cardiomyopathy, or autoimmune disease relatedcardiomyopathy, and side effects due to drug related or toxic-relatedcardiomyopathy), or structural heart disease, valvular heart disease,congenital heart disease, idiopathic pulmonary arterial hypertension,pulmonary hypertension and cardiomyopathy, or associations thereof.Identifying patients with pre-existing LVD is known to those skilled inthe medicinal arts, and such techniques for example may includeassessment of clinical signs and symptoms of heart failure, orechocardiography diagnostic screening.

Pulmonary Capillary Wedge Pressure. Pulmonary capillary wedge pressure,or “PCWP”, provides an estimate of left atrial pressure. Identifyingpatients with pre-existing PCWP is known to those skilled in themedicinal arts, and such techniques for example may include measure byinserting balloon-tipped, multi-lumen catheter (also known as aSwan-Ganz catheter). Measure of PCWP may be used as a means to diagnosethe severity of LVD (sometimes also referred to as left ventricularfailure). PCWP is also a desired measure when evaluating pulmonaryhypertension. Pulmonary hypertension is often caused by an increase inpulmonary vascular resistance (PVR), but may also arise from increasesin pulmonary venous pressure and pulmonary blood volume secondary toleft ventricular failure or mitral or aortic valve disease.

In cardiac physiology, afterload is used to mean the tension produced bya chamber of the heart in order to contract. If the chamber is notmentioned, it is usually assumed to be the left ventricle. However, thestrict definition of the term relates to the properties of a singlecardiac myocyte. It is therefore only of direct relevance in thelaboratory; in the clinic, the term end-systolic pressure is usuallymore appropriate, although not equivalent.

The terms “left ventricular afterload” (and variations thereof) refer tothe pressure that the chamber of the heart has to generate in order toeject blood out of the chamber. Thus, it is a consequence of the aorticpressure since the pressure in the ventricle must be greater than thesystemic pressure in order to open the aortic valve. Everything elseheld equal, as afterload increases, cardiac output decreases. Diseaseprocesses that increase the left ventricular afterload include increasedblood pressure and aortic valve disease. Hypertension (Increased bloodpressure) increases the left ventricular afterload because the leftventricle has to work harder to eject blood into the aorta. This isbecause the aortic valve won't open until the pressure generated in theleft ventricle is higher than the elevated blood pressure. Aorticstenosis increases the afterload because the left ventricle has toovercome the pressure gradient caused by the stenotic aortic valve inaddition to the blood pressure in order to eject blood into the aorta.For instance, if the blood pressure is 120/80, and the aortic valvestenosis creates a trans-valvular gradient of 30 mmHg, the leftventricle has to generate a pressure of 110 mmHg in order to open theaortic valve and eject blood into the aorta. Aortic insufficiencyincreases afterload because a percentage of the blood that is ejectedforward regurgitates back through the diseased aortic valve. This leadsto elevated systolic blood pressure. The diastolic blood pressure wouldfall, due to regurgitation. This would result in an increase pulsepressure. Mitral regurgitation decreases the afterload. Duringventricular systole, the blood can regurgitate through the diseasedmitral valve as well as be ejected through the aortic valve. This meansthat the left ventricle has to work less to eject blood, causing adecreased afterload. Afterload is largely dependent upon aorticpressure.

An intra-aortic balloon pump (IABP) is a mechanical device that is usedto decrease myocardial oxygen demand while at the same time increasingcardiac output. By increasing cardiac output it also increases coronaryblood flow and therefore myocardial oxygen delivery. It consists of acylindrical balloon that sits in the aorta and counterpulsates. That is,it actively deflates in systole increasing forward blood flow byreducing afterload thus, and actively inflates in diastole increasingblood flow to the coronary arteries. These actions have the combinedresult of decreasing myocardial oxygen demand and increasing myocardialoxygen supply. The balloon is inflated during diastole by a computercontrolled mechanism, usually linked to either an ECG or a pressuretransducer at the distal tip of the catheter; some IABPs, such as theDatascope System 98XT, allow for asynchronous counterpulsation at a setrate, though this setting is rarely used. The computer controls the flowof helium from a cylinder into and out of the balloon. Helium is usedbecause its low viscosity allows it to travel quickly through the longconnecting tubes, and has a lower risk of causing a harmful embolismshould the balloon rupture while in use. Intraaortic ballooncounterpulsation is used in situations when the heart's own cardiacoutput is insufficient to meet the oxygenation demands of the body.These situations could include cardiogenic shock, severe septic shock,post cardiac surgery and numerous other situations.

Patients eligible for treatment with iNO. In general, patients approvedfor treatment of iNO are term and near-term (>34 weeks gestation)neonates having hypoxic respiratory failure associated with clinical orechocardiographic evidence of pulmonary hypertension, a condition alsoknown as persistent pulmonary hypertension in the newborn (PPHN). Due tothe selective, non-systemic nature of iNO to reduce pulmonaryhypertension, physicians skilled in the art further employ INOmax® totreat or prevent pulmonary hypertension and improve blood O₂ levels in avariety of other clinical settings, including in both pediatric andadult patients suffering from acute respiratory distress syndrome(ARDS), pediatric and adult patients undergoing cardiac or transplantsurgeries, pediatric and adult patients for testing to diagnosereversible pulmonary hypertension, and in pediatric patients withcongenital diaphragmatic hernia. In most, if not all, of theseapplications, INOmax® acts by preventing or treating reversiblepulmonary vasoconstriction, reducing pulmonary arterial pressure andimproving pulmonary gas exchange.

A small proportion of INOmax® sales stem from its use by clinicians in apremature infant population. In these patients, INOmax® is generallyutilized by physicians as a rescue therapy primarily to vasodilate thelungs and improve pulmonary gas exchange. Some physicians speculate thatINOmax® therapy may promote lung development and/or reduce or preventthe future development of lung disease in a subset of these patients.Although the precise mechanism(s) responsible for the benefits ofINOmax® therapy in these patients is not completely understood, itappears that the benefits achieved in at least a majority of thesepatients are due to the ability of INOmax® to treat or preventreversible pulmonary vasoconstriction.

In clinical practice, the use of INOmax® has reduced or eliminated theuse of high risk systemic vasodilators for the treatment of PPHN.INOmax®, in contrast to systemic vasodilators, specifically dilates thepulmonary vasculature without dilating systemic blood vessels. Further,iNO preferentially vasodilates vessels of aveoli that are aerated, thusimproving V/Q matching. In contrast, systemic vasodilators may increaseblood flow to atelectatic (deflated or collapsed) alveoli, therebyincreasing V/Q mismatch and worsening arterial oxygenation. (See Rubin LJ, Kerr K M, Pulmonary Hypertension, in Critical Care Medicine:Principles of Diagnosis and Management in the Adult, 2d Ed., Parillo JE, Dellinger R P (eds.), Mosby, Inc. 2001, pp. 900-09 at 906; Kinsella JP, Abman S H, The Role of Inhaled Nitric Oxide in Persistent PulmonaryHypertension of the Newborn, in Acute Respiratory Care of the Neonate: ASelf-Study Course, 2d Ed., Askin D F (ed.), NICU Ink Book Publishers,1997, pp. 369-378 at 372-73).

INOmax® also possesses highly desirable pharmacokinetic properties as alung-specific vasodilator when compared to other ostensibly“pulmonary-specific vasodilators.” For example, the short half-life ofINOmax® allows INOmax® to exhibit rapid “on” and “off” responsesrelative to INOmax® dosing, in contrast to non-gaseous alternatives. Inthis way, INOmax® can provide physicians with a useful therapeutic toolto easily control the magnitude and duration of the pulmonaryvasodilatation desired. Also, the nearly instantaneous inactivation ofINOmax® in the blood significantly reduces or prevents vasodilatation ofnon-pulmonary vessels.

The pivotal trials leading to the approval of INOmax® were the CINRGIand NINOS study.

CINRGI study. (See Davidson et al., March 1998, Inhaled Nitric Oxide forthe Early Treatment of Persistent Pulmonary Hypertension of the termNewborn; A Randomized, Double-Masked, Placebo-Controlled, Dose-Response,Multicenter Study; PEDIATRICS Vol. 101, No. 3, p. 325).

This study was a double-blind, randomized, placebo-controlled,multicenter trial of 186 term and near-term neonates with pulmonaryhypertension and hypoxic respiratory failure. The primary objective ofthe study was to determine whether INOmax® would reduce the receipt ofextracorporeal membrane oxygenation (ECMO) in these patients. Hypoxicrespiratory failure was caused by meconium aspiration syndrome (MAS)(35%), idiopathic persistent pulmonary hypertension of the newborn(PPHN) (30%), pneumonia/sepsis (24%), or respiratory distress syndrome(RDS) (8%). Patients with a mean PaO₂ of 54 mm Hg and a mean oxygenationindex (OI) of 44 cm H₂O/mm Hg were randomly assigned to receive either20 ppm INOmax® (n=97) or nitrogen gas (placebo; n=89) in addition totheir ventilatory support. Patients that exhibited a PaO₂>60 mm Hg and apH<7.55 were weaned to 5 ppm INOmax® or placebo. The primary resultsfrom the CINRGI study are presented in Table 4. ECMO was the primaryendpoint of the study.

TABLE 1 Summary of Clinical Results from CINRGI Study Placebo INOmax ® Pvalue Death or ECMO 51/89 (57%) 30/97 (31%) <0.001 Death 5/89 (6%) 3/97(3%) 0.48

Significantly fewer neonates in the ECMO group required ECMO, andINOmax® significantly improved oxygenation, as measured by PaO₂, OI, andalveolar-arterial gradient.

NINOS study. (See Inhaled Nitric Oxide in Full-Term and Nearly Full-TermInfants with Hypoxic Respiratory Failure; NEJM, Vol. 336, No. 9, 597).

The Neonatal Inhaled Nitric Oxide Study (NINOS) group conducted adouble-blind, randomized, placebo-controlled, multicenter trial in 235neonates with hypoxic respiratory failure. The objective of the studywas to determine whether iNO would reduce the occurrence of death and/orinitiation of ECMO in a prospectively defined cohort of term ornear-term neonates with hypoxic respiratory failure unresponsive toconventional therapy. Hypoxic respiratory failure was caused by meconiumaspiration syndrome (MAS; 49%), pneumonia/sepsis (21%), idiopathicprimary pulmonary hypertension of the newborn (PPHN; 17%), orrespiratory distress syndrome (RDS; 11%). Infants≦14 days of age (mean,1.7 days) with a mean PaO₂ of 46 mm Hg and a mean oxygenation index (OI)of 43 cm H₂O/mmHg were initially randomized to receive 100% O₂ with(n=114) or without (n=121) 20 ppm NO for up to 14 days. Response tostudy drug was defined as a change from baseline in PaO₂ 30 minutesafter starting treatment (full response=>20 mmHg, partial=10−20 mm Hg,no response=<10 mm Hg). Neonates with a less than full response wereevaluated for a response to 80 ppm NO or control gas. The primaryresults from the NINOS study are presented in Table 2.

TABLE 2 Summary of Clinical Results from NINOS Study Control NO (n =121) (n = 114) P value Death or ECMO *, † 77 (64%) 52 (46%) 0.006 Death20 (17%) 16 (14%) 0.60 ECMO 66 (55%) 44 (39%) 0.014 * Extracorporealmembrane oxygenation † Death or need for ECMO was the study's primaryend point

Adverse Events from CINRGI & NINOS. Controlled studies have included 325patients on INOmax® doses of 5 to 80 ppm and 251 patients on placebo.Total mortality in the pooled trials was 11% on placebo and 9% onINOmax®, a result adequate to exclude INOmax® mortality being more than40% worse than placebo.

In both the NINOS and CINRGI studies, the duration of hospitalizationwas similar in INOmax® and placebo-treated groups.

From all controlled studies, at least 6 months of follow-up is availablefor 278 patients who received INOmax® and 212 patients who receivedplacebo. Among these patients, there was no evidence of an AE oftreatment on the need for re-hospitalization, special medical services,pulmonary disease, or neurological squeal.

In the NINOS study, treatment groups were similar with respect to theincidence and severity of intracranial hemorrhage, Grade IV hemorrhage,per ventricular leukomalacia, cerebral infarction, seizures requiringanticonvulsant therapy, pulmonary hemorrhage, or gastrointestinalhemorrhage.

The table below shows adverse reactions that occurred in at least 5% ofpatients receiving INOmax® in the CINRGI study. None of the differencesin these adverse reactions were statistically significant when iNOpatients were compared to patients receiving placebo.

TABLE 3 ADVERSE REACTIONS ON THE CINRGI TRIAL Placebo Inhaled NO AdverseReaction (n = 89) (n = 97) Atelectasis 5 (4.8%) 7 (6.5%) Bilirubinemia 6(5.8%) 7 (6.5%) Hypokalemia 5 (4.8%) 9 (8.3%) Hypotension 3 (2.9%) 6(5.6%) Thrombocytopenia 20 (19.2%) 16 (14.8%)

Post-Marketing Experience. The following AEs have been reported as partof the post-marketing surveillance. These events have not been reportedabove. Given the nature of spontaneously reported post-marketingsurveillance data, it is impossible to determine the actual incidence ofthe events or definitively establish their causal relationship to thedrug. The listing is alphabetical: dose errors associated with thedelivery system; headaches associated with environmental exposure ofINOmax® in hospital staff; hypotension associated with acute withdrawalof the drug; hypoxemia associated with acute withdrawal of the drug;pulmonary edema in patients with CREST syndrome.

An analysis of AEs and SAEs from both the CINRGI and NINOS studies, inaddition to post-marketing surveillance, did not suggest that patientswho have pre-existing LVD could experience an increased risk of AEs orSAEs. Nor was it predictable to physicians skilled in the art thatpatients having pre-existing LVD (possibly identified as those patientshaving a PCWP greater than 20 mmHg) should be evaluated in view of thebenefit versus risk of using iNO in patients with clinically significantLVD, and that these patients should be evaluated on a case by casebasis.

Example 1 INOT22 Study

The INOT22, entitled “Comparison of supplemental oxygen and nitric oxidefor inhalation plus oxygen in the evaluation of the reactivity of thepulmonary vasculature during acute pulmonary vasodilatory testing” wasconducted both to access the safety and effectiveness of INOmax® as adiagnostic agent in patients undergoing assessment of pulmonaryhypertension (primary endpoint), and to confirm the hypothesis that iNOis selective for the pulmonary vasculature (secondary endpoint).

During, and upon final analysis of the INOT22 study results, applicantsdiscovered that rapidly decreasing the pulmonary vascular resistance,via the administration of iNO to a patient in need of such treatment,may be detrimental to patients with concomitant, pre-existing LVD.Therefore, a precaution for patients with LVD was proposed to beincluded in amended prescribing information for INOmax®. Physicians werefurther informed to consider reducing left ventricular afterload tominimize the occurrence of pulmonary edema in patients with pre-existingLVD.

In particular, the INOT22 protocol studied consecutive childrenundergoing cardiac catheterization that were prospectively enrolled at16 centers in the US and Europe. Inclusion criteria: 4 weeks to 18 yearsof age, pulmonary hypertension diagnosis, i.e. either idiopathicpulmonary hypertension (IPAH) or related to congenital heart disease(CHD) (repaired or unrepaired) or cardiomyopathy, with pulmonaryvascular resistance index (PVRI)>3 u-m². Later amendments, as discussedherein, added an additional inclusionary criteria of a PCWP less than 20gmm Hg. Patients were studied under general anaesthesia, or withconscious sedation, according to the practice of the investigator.Exclusion criteria: focal infiltrates on chest X-ray, history ofintrinsic lung disease, and/or currently taking PDE-5 inhibitors,prostacyclin analogues or sodium nitroprusside. The study involvedsupplemental O₂ and NO for inhalation plus O₂ in the evaluation of thereactivity of the pulmonary vasculature during acute pulmonaryvasodilator testing. Consecutive children undergoing cardiaccatheterization were prospectively enrolled at 16 centers in the US andEurope. As hypotension is expected in these neonatal populations, thecomparison between iNO and placebo groups is difficult to assess. Aspecific secondary endpoint was evaluated in study INOT22 to provide amore definitive evaluation.

The primary objective was to compare the response frequency with iNO andO₂ vs. O₂ alone; in addition, all subjects were studied with iNO alone.Patients were studied during five periods: Baseline 1, Treatment Period1, Treatment Period 2, Baseline 2 and Treatment Period 3. All patientsreceived all three treatments; treatment sequence was randomized bycenter in blocks of 4; in Period 1, patients received either NO alone orO₂ alone, and the alternate treatment in Period 3. All patients receivedthe iNO and O₂ combination treatment in Period 2. Once the sequence wasassigned, treatment was unblinded. Each treatment was given for 10minutes prior to obtaining hemodynamic measurements, and the BaselinePeriod 2 was at least 10 minutes.

Results for the intent-to-treat (ITT) population, defined as allpatients who were randomized to receive drug, indicated that treatmentwith NO plus O₂ and O₂ alone significantly increased systemic vascularresistance index (SVRI) (Table 4). The change from baseline for NO plusO₂ was 1.4 Woods Units per meter² (WU·m²) (p=0.007) and that for O₂ was1.3 WU·m² (p=0.004). While the change from baseline in SVRI with NOalone was −0.2 WU·m² (p=0.899) which demonstrates a lack of systemiceffect.

TABLE 4 SVRI Change From Baseline by Treatment (Intent-to-Treat)Treatment NO Plus O₂ O₂ NO SVRI (WU · m²) (n = 109) (n = 106) (n = 106)Baseline (room air) Mean 17.2 17.6 18.0 Standard Deviation (SD) 8.869.22 8.44 Median 15.9 16.1 16.2 Minimum, maximum −7.6, 55.6 −7.6, 55.61.9, 44.8 Post-treatment Mean 18.7 18.9 17.8 SD 9.04 8.78 9.40 Median17.1 17.1 15.4 Minimum, maximum   3.0, 47.4   3.9, 43.6 3.3, 50.7 ChangeFrom Baseline Mean 1.4 1.3 −0.2 SD 5.94 5.16 4.65 Median 1.2 1.0 0.2Minimum, maximum −20.5, 19.1  −18.1, 17.7  −12.5, 12.7  p-value^(a)0.007 0.004 0.899 Pairwise comparisons NO plus O₂ versus O₂, p = 0.952NO plus O₂ versus NO, p = 0.014 O₂ versus NO, p = 0.017 ^(a)p-value froma Wilcoxon Signed Rank Test. Only patients with data to determineresponse at both treatments are included in this analysis. Source:INOT22 CSR Table 6.4.1 and Appendix 16.2.6 (ATTACHMENT 1)

The ideal pulmonary vasodilator should reduce PVRI and/or PAPm whilehaving no appreciable effect on systemic blood pressure or SVRI. In thiscase, the ratio of PVRI to SVRI would decrease, given some measure ofthe selectivity of the agent for the pulmonary vascular bed. The changein the ratio of PVRI to SVRI by treatment is shown in Table 5.

TABLE 5 Change in Ratio of PVRI to SVRI by Treatment (Intent-to-Treat)Treatment NO Plus O₂ O₂ NO Ratio PVRI/SVRI (n = 108) (n = 105) (n = 106)Baseline Mean 0.6 0.5 0.6 SD 0.60 0.45 0.56 Median 0.5 0.5 0.4 Minimum,Maximum −1.6, 4.7 −1.6, 1.8   0.0, 4.7 Post Treatment Mean 0.4 0.4 0.5SD 0.31 0.31 0.46 Median 0.3 0.4 0.3 Minimum, Maximum   0.0, 1.3   0.0,1.4 −1.2, 2.2 Change from Baseline Mean −0.2 −0.1 −0.1 SD 0.52 0.31 0.54Median −0.1 −0.1 0.0 Minimum, Maximum −4.4, 2.0 −1.6, 2.0 −4.4, 1.6 PValue¹ <0.001 <0.001 0.002 ¹Wilcoxon Signed Rank Test Source: INOT22 CSRTable 6.5.1 (ATTACHMENT 2)

All three treatments have a preferential effect on the pulmonaryvascular bed, suggesting that all three are selective pulmonaryvasodilators. The greatest reduction in the ratio was during treatmentwith NO plus O₂, possibly due to the decrease in SVRI effects seen withO₂ and NO plus O₂. These results are displayed as percent change in theratio (See Table 6).

TABLE 6 Percent Change in Ratio of PVRI to SVRI by Treatment(Intent-to-Treat) Treatment NO Plus O₂ O₂ NO Ratio PVRI/SVRI (n = 108)(n = 105) (n = 106) Baseline Mean 0.6 0.5 0.6 SD 0.60 0.45 0.56 Median0.5 0.5 0.4 Minimum, Maximum −1.6, 4.7 −1.6, 1.8   0.0, 4.7 PostTreatment Mean 0.4 0.4 0.5 SD 0.31 0.31 0.46 Median 0.3 0.4 0.3 Minimum,Maximum   0.0, 1.3   0.0, 1.4 −1.2, 2.2 Percent Change from BaselineMean −33.5 −19.3 −6.2 SD 36.11 34.59 64.04 Median −34.0 −21.3 −13.8Minimum, Maximum −122.2, 140.1 −122.7, 93.3  −256.1, 294.1 P Value¹<0.001 <0.001 0.006 ¹Wilcoxon Signed Rank Test Source: INOT22 CSR Table6.5.2 (ATTACHMENT 3)

NO plus O₂ appeared to provide the greatest reduction in the ratio,suggesting that NO plus O₂ was more selective for the pulmonaryvasculature than either agent alone.

Overview of Cardiovascular Safety. In the INOT22 diagnostic study, alltreatments (NO plus O₂, O₂, and NO) were well-tolerated. Seven patientsof 134 treated experienced an AE during the study. These includedcardiac arrest, bradycardia, low cardiac output (CO) syndrome, elevatedST segment (the portion of an electrocardiogram between the end of theQRS complex and the beginning of the T wave) on the electrocardiography(ECG) decreased O₂ saturation, hypotension, mouth hemorrhage andpulmonary hypertension (PH). The numbers of patients and events were toosmall to determine whether risk for AEs differed by treatment,diagnosis, age, gender or race. Eight patients are shown in Table 5 dueto the time period in which events are reported. AEs were reported for12 hours or until hospital discharge (which limits the period in whichsuch events can be reported). There is technically no time limit inwhich SAEs are to be reported. So, there were 7 AEs during the study andat least one SAE after the study.

A total of 4 patients had AEs assessed as being related to study drug.These events included bradycardia, low CO syndrome, ST segment elevationon the ECG, low O₂ saturation, PH and hypotension. All but 2 AEs weremild or moderate in intensity and were resolved. Study treatments hadslight and non-clinically significant effects on vital signs includingheart rate, systolic arterial pressure and diastolic arterial pressure.When an investigator records an AE, they are required to say if (intheir opinion) the event is related to the treatment or not. In thiscase, 4 of 7 were considered by the investigator to be related totreatment.

The upper limit of normal PCWP in children is 10-12 mm Hg and 15 mm Hgin adults. In INOT22, a baseline PCWP value was not included asexclusion criteria. However, after the surprising and unexpectedidentification of SAEs in the early tested patients, it was determinedthat patients with pre-existing LVD had an increased risk ofexperiencing an AE or SAE upon administration (e.g., worsening of leftventricular function due to the increased flow of blood through thelungs). Accordingly, the protocol for INOT22 was thereafter amended toexclude patients with a baseline PCWP greater than 20 mm Hg after onepatient experienced acute circulatory collapse and died during thestudy. The value “20 mm Hg” was selected to avoid enrollment of apediatric population with LVD such that they would be most likelyat-risk for these SAEs.

SAEs were collected from the start of study treatment until hospitaldischarge or 12 hours, whichever occurred sooner. Three SAEs werereported during the study period, and a total of 7 SAEs were reported.Three of these were fatal SAEs and 4 were nonfatal (one of which led tostudy discontinuation). In addition, one non-serious AE also lead todiscontinuation. A list of subjects who died, discontinued orexperienced an SAE is provided in Table 5 below.

TABLE 5 Subjects that died, discontinued or experienced SAEs PatientDiscontinued number AE Serious? Fatal? treatment? 01020 Desaturation(hypoxia) No No Yes 02002 Pulmonary edema Yes No No 04001 Hypotensionand cardiac Yes Yes No arrest 04003 Hypotension and ECG Yes No Yeschanges 04008 Hypotension and Yes Yes No hypoxemia 05002 Hypoxia andbradycardia Yes Yes No (also pulmonary edema) 07003 Cardiac arrest YesNo No 17001 Hypoxia Yes No No

Two of the 3 fatal SAEs were deemed related to therapy. All 4 non-fatalSAEs were also considered related to therapy. The numbers of patientsand events were too small to determine whether risk for SAEs differed bytreatment, diagnosis, age, gender or race. At least two patientsdeveloped signs of pulmonary edema (subjects 05002 and 02002). This isof interest because pulmonary edema has previously been reported withthe use of iNO in patients with LVD, and may be related to decreasingPVRI and overfilling of the left atrium. (Hayward C S et al., 1996,Inhaled Nitric Oxide in Cardiac Failure: Vascular Versus VentricularEffects, J Cardiovascular Pharmacology 27:80-85; Bocchi E A et al.,1994, Inhaled Nitric Oxide Leading to Pulmonary Edema in Stable SevereHeart Failure, Am J Cardiology 74:70-72; and, Semigran M J et al., 1994,Hemodynamic Effects of Inhaled Nitric Oxide in Heart Failure, J Am CollCardiology 24:982-988).

Although the SAE rate is within range for this population, it appearsthat patients with the most elevated PCWP at baseline had adisproportionately high number of these events. (Bocchi E A et al.,1994; Semigran M J et al., 1994).

In the INOT22 study, 10 of the total 134 patients had a baseline PCWP≧18mm Hg (7.5%), of which, 3 subjects (04001, 02002 and 04003) had a SAE orwere prematurely discontinued from the study (30%) compared to 6.5% forthe entire cohort.

Although there were very few significant AEs in the INOT22 study, theseevents are consistent with the expected physiologic changes in patientswith severe LVD. The events also corroborate prior observations that iNOis rapidly acting, selective for the pulmonary vasculature, andwell-tolerated in most patients. The actual incidence of acute LVDduring acute ventricular failure (AVT) is unknown. However, it isreasonable to expect that a significant number of patients are at-riskfor an increased incidence of SAEs upon iNO treatment based upon thenature of the underlying nature of the illness, i.e., pulmonaryhypertension and cardiovascular disease more generally. Thus, it wouldbe advantageous to have physicians identify these patients prior tobeginning iNO treatment, so that the physicians are alerted to thispossible outcome.

Benefits and Risks Conclusions. The INOT22 study was designed todemonstrate the physiologic effects of iNO in a well defined cohort ofchildren (i.e., intended patient population) with pulmonary hypertensionusing a high concentration, 80 ppm, of iNO, i.e., one that would beexpected to have the maximal pharmacodynamic effect. INOT22 was thelargest and most rigorous pharmacodynamic study of iNO conducted todate, and it confirms a number of prior observations, such as iNO beingrapidly acting, selective for the pulmonary vasculature, andwell-tolerated in most patients.

It is also acknowledged that rapidly decreasing the PVR may beundesirable and even dangerous in patients with concomitant LVD. In theINOT22 study, the overall numbers of SAEs and fatal SAEs are within theexpected range for patients with this degree of cardiopulmonary disease.The overall rate is 7/124 (5.6%), which is closely comparable to therate of 6% recently reported in a very similar cohort of patients.(Taylor C J et al., 2007, Risk of cardiac catheterization underanaesthesia in children with pulmonary hypertension, Br J Anaesth98(5):657-61). Thus, the overall rate of SAEs would seem to be moreclosely related to the underlying severity of illness of the patientsrather than to the treatments given during this study.

The INOT22 study results demonstrate that patients who had pre-existingLVD may experience an increased rate of SAEs (e.g., pulmonary edema).During the course of the study, the protocol was amended to excludepatients with a PCWP>20 mmHg. The benefit/risk of using iNO in patientswith clinically significant LVD should be evaluated on a case by casebasis. A reduction in left ventricular afterload may perhaps be appliedto minimize the occurrence of pulmonary edema.

1. A method of reducing the risk of one or more adverse events orserious adverse events in an intended patient population comprisingchildren in need of being treated with inhalation of nitric oxidecomprising excluding from such treatment anyone in the intended patientpopulation having pre-existing left ventricular dysfunction.
 2. A methodof reducing the risk of one or more adverse events or serious adverseevents in an intended patient population comprising children in need ofbeing treated with inhalation of nitric oxide comprising excluding fromsuch treatment anyone in the intended patient population havingpre-existing left ventricular dysfunction, wherein anyone in theintended patient population further has a pulmonary capillary wedgepressure greater than 20 mm Hg.
 3. The method of claim 2, wherein thetreatment further comprises inhalation of oxygen.
 4. The method of claim2, wherein the treatment is delivered using a ventilator.
 5. The methodof claim 2, wherein anyone in the intended patient population havingpre-existing left ventricular dysfunction also have one or moreconditions selected from diastolic dysfunction, hypertensivecardiomyopathy, systolic dysfunction, ischemic cardiomyopathy, viralcardiomyopathy, idiopathic cardiomyopathy, autoimmune disease relatedcardiomyopathy, drug-related cardiomyopathy, toxin-relatedcardiomyopathy, structural heart disease, valvular heart disease,congenital heart disease, idiopathic pulmonary arterial hypertension andpulmonary hypertension cardiomyopathy.
 6. The method of claim 2, whereinthe intended patient population are at risk of one or more adverseevents or serious adverse events selected from pulmonary edema,hypotension, cardiac arrest, electrocardiogram changes, hypoxemia,hypoxia and bradycardia.
 7. The method of claim 2, further comprisingreducing left ventricular afterload to minimize or reduce the risk ofthe occurrence of an adverse event or serious adverse event beingpulmonary edema.
 8. The method of claim 7, wherein the left ventricularafterload is minimized or reduced by administering a pharmaceuticaldosage form comprising nitroglycerin or calcium channel blocker.
 9. Themethod of claim 7, wherein the left ventricular afterload is minimizedor reduced using an intra-aortic balloon pump.
 10. The method of claim2, wherein the intended patient population in need of being treated withthe inhalation of nitric oxide has one or more of idiopathic pulmonaryarterial hypertension characterized by PAPm>25 mm Hg at rest, PCWP≦15 mmHg, and, a PVRI>3 u·m²; congenital heart disease with pulmonaryhypertension repaired and unrepaired characterized by PAPm>25 mm Hg atrest and PVRI>3 u·m²; cardiomyopathy characterized by PAPm>25 mm Hg atrest and PVRI>3 u·m²; or, the patient is scheduled to undergo rightheart catheterization to assess pulmonary vasoreactivity by acutepulmonary vasodilation testing.
 11. A method of reducing the risk of theoccurrence, in a patient being a child of one or more adverse events orserious adverse events associated with a medical treatment comprisinginhalation of nitric oxide, said method comprising: a. identifying apatient eligible for inhalation of nitric oxide treatment; b.determining if said patient has pre-existing left ventriculardysfunction evidenced by an elevated pulmonary capillary wedge pressure;and, c. administering said medical treatment if said patient does nothave pre-existing left ventricular dysfunction; thereby reducing therisk of the adverse event or serious adverse event associated with saidmedical treatment.
 12. The method of claim 11, wherein said patientfurther exhibits a pulmonary capillary wedge pressure greater than 20 mmHg.
 13. The method of claim 11, wherein the patient who has pre-existingleft ventricular dysfunction has one or more conditions selected fromdiastolic dysfunction, hypertensive cardiomyopathy, systolicdysfunction, ischemic cardiomyopathy, viral cardiomyopathy, idiopathiccardiomyopathy, autoimmune disease related cardiomyopathy, side effectsdue to drug-related cardiomyopathy, side effects due to toxin-relatedcardiomyopathy, structural heart disease, valvular heart disease,congenital heart disease, idiopathic pulmonary arterial hypertension,pulmonary hypertension and cardiomyopathy.
 14. The method of claim 12,wherein the patient who has pre-existing left ventricular dysfunctionhas one or more conditions selected from diastolic dysfunction,hypertensive cardiomyopathy, systolic dysfunction, ischemiccardiomyopathy, viral cardiomyopathy, idiopathic cardiomyopathy,autoimmune disease related cardiomyopathy, side effects due todrug-related cardiomyopathy, side effects due to toxin-relatedcardiomyopathy, structural heart disease, valvular heart disease,congenital heart disease, idiopathic pulmonary arterial hypertension,pulmonary hypertension and cardiomyopathy.
 15. The method of claim 11,wherein the medical treatment further comprises inhalation of oxygen.16. The method of claim 11, wherein the treatment is delivered using aventilator.
 17. The method of claim 11, further comprising reducing leftventricular afterload to minimize or reduce the risk of the occurrenceof an adverse event or serious adverse event being pulmonary edema. 18.The method of claim 17, wherein the left ventricular afterload isminimized or reduced by administering a pharmaceutical dosage formcomprising nitroglycerin or calcium channel blocker.
 19. The method ofclaim 17, wherein the left ventricular afterload is minimized or reducedusing an intra-aortic balloon pump.